This invention relates to 1H-benz[de]isoquinoline-2(3H)-acetic acid derivatives, therapeutically acceptable salts thereof, a process for their preparation and to pharmaceutical compositions thereof. The derivatives have pharmacologic properties which render them beneficial for the treatment of diabetes mellitus and associated conditions.
For many years diabetes mellitus has been treated with two established types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. However, the resulting longevity of diabetic patients has led to complications such as neuropathy, nephropathy, retinopathy and cataracts. These complications have been linked to the undesirable accumulation of sorbitol in diabetic tissue, which in turn result from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key enzyme involved in the conversion of hexoses to polyols (the sorbitol pathway) is aldose reductase. J. H. Kinoshita and collaborators, see J. H. Kinoshita, et al., Biochem. Biophys. Acta., 158, 472 (1968) and references cited therein, have demonstrated that aldose reductase plays a central role in the etiology of galactosemic cataracts by effecting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitol in the lens. Furthermore, a relationship between elevated levels of glucose and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R. van Heyningen, Exp. Eye Res., 3, 124 (1964); L. T. Chylack and J. H. Kinoshita, Invest. Ophthal., 8, 401 (1969) and J. D. Ward and R. W. R. Baker, Diabetol., 6, 531 (1970).
1,3-Dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid has been reported to be an effective inhibitor of aldose reductase (see D. Dvornik et al., Science, 182, 1146 (1973) and useful for the treatment of diabetic complications such as diabetic cataracts, neuropathy, nephropathy and retinopathy (see K. Sestanj, N. Simard-Duquesne and D. M. Dvornik, U.S. Pat. No. 3,821,383, June 28, 1974). This compound also stimulates insulin secretion and prevents or decreases the secretion of excessive amounts of glucagon, see W. Lippmann, U.S. Pat. No. 4,118,495, Oct. 3, 1978. Consequently, this compound represents an important adjunct to the treatment of diabetes mellitus. U.S. Pat. No. 3,821,383 also discloses the 5-nitro, 5-amino and 6-bromo derivatives of 1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid. T. Noguchi et al, Chem. Abstr., 72, 56708r (1970) for Japanese Pat. No. 69/18,955, Aug. 18, 1969 discloses, amongst other things, the 6-methoxy derivative of 1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid as a fluorescent whitening agent for fibers.
The present application discloses a new group of 1H-benz[de]isoquinoline compounds which inhibit aldose reductase in the diabetic subject. Some of these compounds beneficially effect the secretions of insulin and glucagon in the diabetic, and also inhibit gastric acid secretion.